Interest In Flavonoids Research Articles

Review of Biological Activity of Flavonoids: Quercetin and Kaempferol

Flavonoids are an extensive class of secondary metabolites present in varying concentrations in different parts of plants. Medicinal raw materials containing flavonoids have been used in traditional medicine in various countries for centuries and are also used in modern medicine for the production of drugs. Compared to other groups of secondary metabolites, flavonoids are often present in relatively large amounts. Interest in flavonoids is driven by constantly updated data on their biological activity and their wide distribution in the plant world. This review focuses on the two most commonly occurring polyphenolic compounds in plants, quercetin and kaempferol. The article describes the main glycosidic forms of the flavonoids under consideration and the modern results of studying their biological activity, namely their antioxidant, anti-allergic, anti-inflammatory, cardioprotective, and anti-tumor properties. In addition, some of the mechanisms for implementing the above types of biological activity are discussed. The analysis suggests that further in-depth pharmacological research on these flavonoids and the development of new advanced drugs based on them is promising. The cores of quercetin and kaempferol can be recommended for chemical modification to obtain highly active compounds with antioxidant, anti-allergic, anti-inflammatory, cardioprotective, and anti-tumor activities. Keywords: flavonoids, quercetin, kaempferol, glycosidic forms, biological activity, antioxidant activity, anti-allergic activity, anti-inflammatory activity, cardioprotective activity, anti-tumor activity, mechanisms of action, drugs, chemical modification.

Effects of Flavonoids in Experimental Models of Arterial Hypertension.

Flavonoids are a class of substances of a vegetal origin with many interesting actions from the point of view of human disease. Interest in flavonoids in the diet has increased in recent years due to the publication of basic, clinical and epidemiological studies that have shown a whole array of salutary effects related to intake of flavonols and flavones as well as a lower morbility and mortality of cardiovascular diseases. Since arterial hypertension is the most common modifiable risk factor for cardiovascular diseases, this review will focus mainly on the effects of flavonoids on the cardiovascular system with relation to the elevation of blood pressure. Its antihypertensive effects as well as the many investigations performed in experimental models of arterial hypertension, are reviewed in this mini-review.

Flavonoids: A Myth or a Reality for Cancer Therapy?

Nutraceuticals are biologically active molecules present in foods; they can have beneficial effects on health, but they are not available in large enough quantities to perform this function. Plant metabolites, such as polyphenols, are widely diffused in the plant kingdom, where they play fundamental roles in plant development and interactions with the environment. Among these, flavonoids are of particular interest as they have significant effects on human health. In vitro and/or in vivo studies described flavonoids as essential nutrients for preventing several diseases. They display broad and promising bioactivities to fight cancer, inflammation, bacterial infections, as well as to reduce the severity of neurodegenerative and cardiovascular diseases or diabetes. Therefore, it is not surprising that interest in flavonoids has sharply increased in recent years. More than 23,000 scientific publications on flavonoids have described the potential anticancer activity of these natural molecules in the last decade. Studies, in vitro and in vivo, show that flavonoids exhibit anticancer properties, and many epidemiological studies confirm that dietary intake of flavonoids leads to a reduced risk of cancer. This review provides a glimpse of the mechanisms of action of flavonoids on cancer cells.

Selectivity of Current Extraction Techniques for Flavonoids from Plant Materials

Flavonoids have a broad spectrum of established positive effects on human and animal health. They find an application in medicine for disease therapy and chemoprevention, whence the interest in flavonoids increases. In addition, they are used in food and cosmetic industries as pigments and biopreservatives. Plants are an inexhaustible source of flavonoids. The most important step of plant raw material processing is extraction and isolation of target compounds. The quality of an extract and efficiency of a procedure are influenced by several factors: Plant material and pre-extracting sample preparation, type of solvent, extraction technique, physicochemical conditions, etc. The present overview discusses the common problems and key challenges of the extraction procedures and the different mechanisms for selective extraction of flavonoids from different plant sources. In summary, there is no universal extraction method and each optimized procedure is individual for the respective plants. For an extraction technique to be selective, it must combine an optimal solvent or mixture of solvents with an appropriate technique. Last but not least, its optimization is important for a variety of applications. Moreover, when the selected method needs to be standardized, it must achieve acceptable degree of repeatability and reproducibility.

Flavonoid-Rich Extract of Actinidia macrosperma (A Wild Kiwifruit) Inhibits Angiotensin-Converting Enzyme In Vitro.

Increasing interest in flavonoids in kiwifruit is due to the health-promoting properties of these bioactives. Inhibition of the angiotensin-converting enzyme (ACE) is one of the main therapeutic targets in controlling hypertension. The present study investigated the ACE inhibitory activity of flavonoid-rich extracts obtained from different kiwifruit genotypes. The flavonoid-rich extracts were prepared from fruits of Actinidia macrosperma, Actinidia deliciosa cv Hayward (Green kiwifruit), and Actinidia chinensis cv Hort 16A (Gold kiwifruit) by steeping the lyophilized fruit samples in 70% aqueous acetone, followed by partitioning the crude extracts with hexane. The composition of each extract was analyzed using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). The ACE inhibitory activity of the fruit extracts was performed using a fluorescence-based biochemical assay. The subclass flavonol was the most abundant group of flavonoids detected in all the extracts tested from three different kiwifruit cultivars. Quercetin-3-O-galactoside, quercetin-3-O-glucoside, quercetin-3-O-rhamnoside, quercetin-3-O-rutinoside, quercetin-3-O-arabinoglucoside, catechin, epigallocatechin gallate, epigallocatechin, chlorogenic, ferulic, isoferulic, and caffeic acid were prominent phenolics found in A. macrosperma kiwifruit. Overall, the flavonoid-rich extract from A. macrosperma showed a significantly (p < 0.05) high percentage of inhibition (IC50 = 0.49 mg/mL), and enzyme kinetic studies suggested that it inhibits ACE activity in vitro. The kiwifruit extracts tested were found to be moderately effective as ACE inhibitors in vitro when compared to the other plant extracts reported in the literature. Further studies should be carried out to identify the active compounds from A. macrosperma and to validate the findings using experimental animal models of hypertension.

Development and Validation of an HPLC-DAD Analysis for Flavonoids in the gel of Scutia buxifolia.

Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables and tea, and are an integral part of the human diet. Quercetin and rutin are bioactive markers of Scutia buxifolia and no analytical methods reported so far, associated with quality control of polyherbal formulations containing this species. Therefore, there is a need to develop a sensitive, simple, rapid and reliable method that can simultaneously determine these markers in their combinations. A high-performance liquid chromatography method has been developed and validated as per ICH guidelines. The chromatographic analysis was performed using a C18 column, the mobile phase system consisted of acetonitrile-water (70 : 30, v/v) containing 0.5% (v/v) phosphoric acid and quercetin and rutin were quantificadoa to 356 nm. The proposed method for the quantification of quercetin and rutin in the S. buxifolia fraction (EaSb) and gel was linear, sensitive, precise, specific, accurate and robust. This validated method can be used to control the quality of the EaSb and the gel.

Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties

Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet.Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis.

Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemistry and pharmacology

Multidrug resistance (MDR) represents one of the major problems in pharmacotherapy of important diseases (e.g., cancer, epilepsy). Although many factors may contribute to the development of MDR phenotype, the increased expression and/or functional activity of P-glycoprotein (P-gp; active drug efflux transporter) across the cell membrane has been recognized as the main one. Therefore, a great attention has been given to the search of P-gp inhibitors as therapeutic agents to reverse the MDR mediated by P-gp. Since the chemical entities identified over the last three decades as potential P-gp inhibitors did not show suitable pharmacological properties, more recently herbal components, such as flavonoid compounds, have gained a great interest as safe P-gp inhibitors. The interest in flavonoids as P-gp inhibitors is increasing due to their potential favourable characteristics, including selectivity and non-cytotoxic effects. Flavonoids integrate the third-generation non-pharmaceutical category of P-gp inhibitors, and some of them exhibited effects comparable to those of the classic P-gp inhibitors. In fact, some flavonoids found in foods and beverages of herbal origin appear to be quite promising to inhibit the P-gp–mediated drug efflux, indicating their potential value to enhance the systemic/cellular bioavailability of P-gp drug substrates when administrated in co-therapy. This review paper summarizes the current evidence of P-gp inhibitory effects produced by flavonoids, taking into account studies performed in cell-based in vitro models, in vivo animal models and clinical trials.

Flavonoid Basics: Chemistry, Sources, Mechanisms of Action, and Safety

In our efforts to understand how various dietary factors can influence the risk and progression of chronic disease, much recent research has focused on phytochemicals. Phytochemicals are defined as nonessential nutrients found in plant-based food, many of which have been established as bioactive and thus may affect human health (1). The largest group of phytochemicals is the polyphenols, comprised principally of the flavonoids, which are characterized chemically by two benzene rings joined by a linear carbon chain. Evidence from observational studies indicates that regular consumption of foods containing flavonoids may reduce the risk several chronic conditions, including neurodegenerative diseases (2), atherosclerosis (3), and certain forms of cancer (4). These results have generated considerable interest in flavonoids, although much basic information about their nutrient characteristics in humans remains limited, e.g., their bioavailability and metabolism, interactions with other dietary factors, mechanisms of action, and intakes associated with specific health outcomes. Although flavonoids are commonly defined as dietary antioxidants and their putative health benefits commonly attributed to this mechanism, it now appears their principal actions are mediated in vivo via other biochemical and molecular pathways (5).

Review of flavonoids and other phenolics from fruits of different tomato (Lycopersicon esculentum Mill.) cultivars

AbstractBACKGROUND: Tomato, one of the most important vegetables worldwide, contains a range of flavonoids and phenolic acids in addition to lycopene, which are regarded as potentially useful compounds with respect to health benefits. Composition data in fresh tomatoes vary due to genetic and environmental factors and cultural practices. Breeding programs aim to produce tomatoes with enhanced levels of flavonoids and other phenolics.RESULTS: The present paper gives an overview of flavonoids, stilbenoids and other phenolics reported to occur in tomato fruits. Contents are reported for a wide range of cultivars and types. Metabolism of phenolics during fruit maturation and tissue location are described, and an overview of measured contents is given. Effects of environmental conditions and cultural practices are estimated using available literature. Recent literature on transgenic tomatoes is included, and possibilities for regulating phenolic contents in tomatoes are discussed.CONCLUSION: The literature review clearly discloses a rapidly growing interest in flavonoids and other phenolics in tomato fruits and products made thereof. This is particularly connected to the antioxidant properties of these compounds as well as other possible health effects. Choice of cultivar and effects of environment and agronomic practices are important factors with respect to phenolic qualities and quantities of tomatoes. Copyright © 2009 Society of Chemical Industry

7-(3-Benzyloxypropyl)apigenin, A Novel Cytotoxic Flavone Derivative

In recent years, there has been a resurgence of scientific interest in flavonoids, which is due to the association of these compounds with a wide range of health promoting effects. Among those, much of the interest in flavonoids has recently been focused on their anticancer properties. Different mechanisms have been linked to flavonoidmediated cytotoxicity, including their antioxidant activities, their effects on signal transduction pathways involved in cell proliferation and angiogenesis, as well as their modulation of aromatase activity, a key enzyme involved in estrogen biosynthesis, and the enzymes required for metabolic activation of procarcinogens and the detoxification of carcinogens. Even though multiple mechanisms account for flavonoidinduced cytotoxicity, disruption of the signal transduction pathway for cell proliferation by inhibition of the cyclindependent kinases (CDKs) has drawn special attention since the discovery of a synthetic flavonoid flavopiridol as a potent anticancer agent. Flavopiridol demonstrated potent in vitro inhibition of all cyclin-dependent kinases (CDKs) tested (CDKs 1, 2, 4 and 7), and clearly blocked cell cycle progression at the G1/S and G2/M boundaries. However, in spite of flavopiridol’s potent activity, two major challenges remain: more potent and specific inhibition of the kinase targets. The crystal structure of the flavopiridol analogue, deschloroflavopiridol, co-crystallized with CDK2, reveals the key hydrogen bonds. In comparison with the other CDK2 inhibitors, desflavopiridol has additional hydrogen bonds around the C8-substituent (Fig. 1). As a result, in order to enhance the selectivity and binding affinity of the flavopiridol analogues against the target kinase, structural modifications at the C2 and C8 positions of the flavone core have been extensively pursued. However, little effort has been made to modify other positions of the flavone scaffold such as the most reactive nearby O7 position. In our previous virtual screening study against CDK2, we found a possible hydrophobic binding pocket composed of Phe80 and Phe146 inside the ATPbinding site (yellow ellipse, Fig. 2). Intriguingly, docking study of several flavonoid derivatives suggested that flavonoids with O7-substituent with optimum chain length would probably fit into this pocket (Fig. 2) to show increases in both selectivity and binding affinity against CDK2. Thus, in this study, we designed a flexible propyloxybenzyl linker which would locate its terminal aromatic ring in the proposed hydrophobic pocket. Also, an oxygen atom placed in the middle of the propyloxybenzyl linker is expected to have a dual role: formation of an additional hydrogen bonding interaction with backnone NH of Asp145 and enhancement of the solubility of the flavonoid. For the synthesis of the title compound, commercially available apigenin was initially used as a starting material, but alkylation under basic conditions usually provided dialkylated product at the 7-O and 4-O positions (data not shown). Thus, the synthetic plan was changed to regioselective alkylation of flavanone naringenin (1, Fig. 3) followed

Superoxide Radical Scavenging Properties of Extracts and Flavonoids Isolated from the Leaves of Blumea balsamifera.

In view of the pharmacological interest in flavonoids, the superoxide radical scavenging capacity of pet-ether, chloroform, and methanol extracts and flavonoids of Blumea balsamifera. DC leaves on nonenzymatically (phenazine methosulfate/NADH) generated superoxide radicals were evaluated. The methanol extract (93.91 ± 1.37%) exhibited higher radical scavenging activity than the chloroform extract (84.58 ± 1.51%). The pet-ether extract was inactive toward nonenzymatically generated superoxide radicals. The superoxide radical scavenging capacity of flavonoids (100 µM) as determined was decreased in the order quercetin > luteolin > 5,7,3′,5′-tetrahydroxyflavanone > blumeatin > rhamnetin > tamarixetin > luteolin-7-methyl ether > dihydroquercetin-4′-methyl ether > dihydroquercetin-4′,7-dimethyl ether. It was concluded that flavonoids with a free hydroxyl group were more active than methylated compounds and that the flavonoid content of extracts contributed to their superoxide radical scavenging activity.

Superoxide Radical Scavenging Properties of Extracts and Flavonoids Isolated from the Leaves of Blumea balsamifera

In view of the pharmacological interest in flavonoids, the superoxide radical scavenging capacity of pet-ether, chloroform, and methanol extracts and flavonoids of Blumea balsamifera DC leaves on nonenzymatically (phenazine methosulfate/NADH) generated superoxide radicals were evaluated. The methanol extract (93.91 ± 1.37%) exhibited higher radical scavenging activity than the chloroform extract (84.58 ± 1.51%). The pet-ether extract was inactive toward nonenzymatically generated superoxide radicals. The superoxide radical scavenging capacity of flavonoids (100 µM) as determined was decreased in the order quercetin > luteolin > 5,7,3′,5′-tetrahydroxyflavanone > blumeatin > rhamnetin > tamarixetin > luteolin-7-methyl ether > dihydroquercetin-4′-methyl ether > dihydroquercetin-4′,7-dimethyl ether. It was concluded that flavonoids with a free hydroxyl group were more active than methylated compounds, and the flavonoid content of extracts contributed to their superoxide radical scavenging activity.

Potential health impacts of excessive flavonoid intake

Plant flavonoids are common dietary components that have many potent biological properties. Early studies of these compounds investigated their mutagenic and genotoxic activity in a number of in vitro assays. Recently, a renewed interest in flavonoids has been fueled by the antioxidant and estrogenic effects ascribed to them. This has led to their proposed use as anticarcinogens and cardioprotective agents, prompting a dramatic increase in their consumption as dietary supplements. Unfortunately, the potentially toxic effects of excessive flavonoid intake are largely ignored. At higher doses, flavonoids may act as mutagens, pro-oxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism. Thus, in high doses, the adverse effects of flavonoids may outweigh their beneficial ones, and caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet. The unborn fetus may be especially at risk, since flavonoids readily cross the placenta. More research on the toxicological properties of flavonoids is warranted given their increasing levels of consumption.

Molecular Structure and Proton Affinities of the 4H-1-Benzopyran-4-one Molecule and Its Hydroxylated Derivatives.

Flavonoids are a class of low molecular weight phenolic compounds widely distributed in the plant kingdom.1 They have displayed potential pharmacological applications as antibacterial, antioxidant, anticancer, and antiallergy agents.2-6 Furthermore, there has been a considerable recent interest in flavonoids since substantial evidence has been accumulated that they exhibit anti-HIV activity.7,8 These compounds consists of a benzene ring fused with a γ-pyrone ring, which are usually denoted Aand C-rings, respectively. The most important chemical property of these compounds is the enhanced reactivity of the C-ring, which was discovered more than 30 years ago.9-12 More specifically, the strong acid/base properties of the C-ring were considered particularly relevant since protonation of substrates occurs during numerous biochemical processes and, in some cases, is the key step of the entire process. On the other hand, the molecular geometries and the electronic structures of 1-3 were investigated at both semiempirical13,14 and ab initio levels using a minimal basis set.15 Furthermore, the solvation of 1 was recently investigated using combined SCRF/ Discrete methods.16 Nevertheless, there are some questions related to chemical properties of flavonoids that remain unknown. Thus, the site of protonation of flavonoids is obscure, although experimental studies in γ-pyrone derivatives10-12 suggest that the protonation occurs not in the heterocyclic oxygen but on the carbonyl oxygen. On the other hand, the possible existence of π-conjugation in the C-ring has not been ascertained. These points are of crucial interest to understand both the chemical and biological properties of flavonoids. This work describes the results of a quantum mechanical study about the acid/base properties of flavonoids in the gas phase and aqueous solution. For this purpose, three of the most important flavonoids were selected: 4H-1-benzopyran-4-one (1), 2-hydroxy-4H-1-benzopyran-4-one (2), and 3-hydroxy-4H-1-benzopyran-4-one (3). Furthermore, the existence of π-conjugation in the C-ring has been also investigated.